4-thiazolidone-2-n-caproates and preparation thereof



Patented Nov. 11 1952 PREPARATION THEREOF Robert Clark,

'11,.111 ass'igr'iors to Abbott Laboratories,

North Chicago, 111., a corporation of Illinois Drawing. ApplicationMarch 31, 1951, Serial No. 218,698

i i LL This invent on relate t 1 1 5 1 .d rl

rs Q? (l-thiazolidone 2 n-caproic acid and methods of manufacturethereof. Among the objects and y v ent invention a novel process forproducing new and novel esters of 4-thiazolidone-2-ncaproic acid havingtherapeutic properties per se, and which are also .intermediates for themanu facture of other organiccompounds. The class of compounds withwhich, the invention is concerned may be represented by the formula:

0=(|J-\NH in which R. islower alkoxy and amine including substitutedamines. In general, the ester compound of the invention may be preparedby the reaction of thioglycolamide with a lower alkyl ester ofw-fOIIIlYl caproic acid. The amides are prepared by aminating the esterwith ammonia or substituted ammonia to form the corresponding amide. Inmore specific detail, the followin examples illustrate the invention:

Example I About 30 g. of the w-carbalkoxy acid chloride of caproic acid,6-carbethoxy caproyl chloride is dissolved in about 200 ml. of dryxylene, and about 3 g. of palladium on barium sulfate is suspendedtherein. The air in the reaction vessel is replaced with hydrogen, andthe solution is heated to about 115 C. with stirring. The stirring iscontinued for about 2% hours, in which time about 90% of the hydrogenchloride from the reaction is evolved. The reaction mixture is cooled,filtered, and the xylene removed under reduced pressure. Theethyl-w-formyl caproate distills at 55-57 at 1 mm. of mercury.

Example II About 7 g. of thioglycolamide and about 11 g. ofethyl-w-formyl caproate (obtained from Example I) are mixed together in50 ml. of xylene. The solution is refluxed for about an hour. Thereaction mixture is then distilled, recovering the product boiling above170 The ethyl 4-thiazolidone-2-n-caproate is recrystallized from asolution of one part benzene and about 3 parts of Skellysolve B, meltingpoint 49-50 C.

Example III Following the procedure of Example I I, methyl4-thiazolidone-2-n-caproate may be prepared by advantage; or the ies; I

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reacting thioglycolamide and methyl formyl caproate, melting id-47 C.

r wi lvt H. a eft ube-.2 wa ti eet pared accordingto-th procedure. ofexa ple II by reacting .thioglycolamide andbutyl ,tJ-formyl aldehyde.The product is a viscous 'oil.

r ErampleV I About 200 .me .oru u' hazo uonea esta .ar so, 'ed-ii a out1:111. .01: c n trated,;-ammonium,hydroxide and. about ,3 m1. a lute t hw e ac o mi fiuiie is war ed to about 40 0., and allowed to standforabout3 days. The mixture is evaporated to dryness, and the resulting4-thiazolidone-2-n-caproamide is recrystallized from aqueous ethanol,melting point 150155 C.

Example VI Following the procedure of Example V and substitutingmethylamine for the ammonium hydroxide, i-thiazolidone 2N-methyl-n-caproamide is obtained; melting point -146 C.

The esters, i. e. the methyl, ethyl, etc. esters of4-thiazolidone-2-n-caproic acid, may be hydrolyzed to the acid, as byheating the esters with potassium hydroxide in methanol. Other esters oramides may then be produced directly from the acid thus obtained.

Other substituted amides of 4-thiazolidone-2- n-caproic acid may beobtained by aminating an alkyl ester of the acid with a substitutedammonia compound to form the corresponding amide. For instance,4-thiazolidone-2-N-ethyln-caproamide is produced by aminating ethyl4-thiazolidone-Z-n-caproate with ethylamine; 4-thiazolidone-2-N-propyl-n-caproamide with propylamine;4-thiazolidone-2-N-dimethyl-n-caproamide with dimethylamine;4-thiazolidone-2-N- diethyl-n-caproamide with diethylamine;4-thiazolidone-Z-N-dipropyl-n-caproamide with dipropylamine; etc.

The carbon atom in the thiazolidone ring substituted with caproic acidradical is an asymmetrical carbon atom, i. e., substituted with fourdifierent substituents, and the compound therefore exists in two forms,as stereoisomers. The products of the present invention are produced asa racemic mixture, i. e. equal parts of the d and Z form, and may beresolved, if desired, into either component accordin to known methods ofresolution.

The 4-thiazolidone-2-n-caproic acid, described in copending applicationS. N. 190,972, filed Octoher 19, 1950, entitled Composition of Matter,shows activity against certain micro-organisms. In comparison with theacid, ethyl l-thiazolidone-2-n-caproate shows about twice the activity,and the 4-thiazolidone-2-n-caproamide shows about two to four times theactivity of the acid against the microorganisms.

Others may readily adapt the invention for use under various conditionsof service, by employing one or more of the novel features disclosed orequivalents thereof. As at present advised with respect to the apparentscope of our invention, we desire to claim the following subject matter.

We claim:

1. A compound of the formula wherein R is a functional group selectedfrom the class consisting of OCH3, --OC2H5, -OC3H7, OC4H9, NH2, NHCH3,--NHC2H5, -NHC3H1, N(CH3)2, N(C2H5) 2, and N(C3I-Im)z.

2. Ethyl 4-thiazolidone-2-n-caproate.

3. Methyl 4-thiazolidone-2-n-caproate.

Butyl 4-thiazolidone-2-n-caproate. 4.-Thiazolidone-2-n-capr0amide.l-Thiazolidone-2-N-methyl-n-caproamide. The process which compriseshydrogenating an w-carbalkoxy acid chloride of caproic acid to form alower alkyl ester of w-formyl caproic acid, and heating the resultantaldehyde with thioglycolamide to produce a lower alkyl4-thiazolidone-2-n-caproate.

down

'4 8. The method of preparing a compound of the formula O: NH

wherein R is a lower alkyl, which comprises heating thioglycolamide witha lower alkyl ester of w-formal caproic acid.

9. The process which comprises heating ethyl w-formyl caproate withthioglycolamide to produce ethyl 4-thiazolidone-2-n-caproate.

10. The process which comprises heating methyl w-formyl caproate withthioglycolamide to produce methyl 4-thiazolidone-2-n-caproate.

11. The process which comprises heating butyl w-formyl caproate withthioglycolamide to produce butyl 4-thiazolidone-2-n-caproate.

12. The process which comprises heating a lower alkyl ester ofw-fOI'lIlYl caproic acid with thioglycolamide to produce a dl-low esterof 4-thiazolidone-Z-n-caproic acid, and aminating the said ester toproduce the dl-4-thiazolidone-2-ncaproamide.

JAY R. SCI-IENCK. ROBERT K. CLARK, JR.

REFERENCES CITED The following references are of record in the file ofthis patent:

Boehm et al., Chem. Abstracts, vol. 28, page 1033 (1934).

Harris et al., Chem. Abstracts, vol. 40, page 1496 (1946).

1. A COMPOUND OF THE FORMULA 